This invention relates to novel polymeric bioactive agent carriers. More particularly, the invention relates to cyclodextrin-grafted biocompatible polymers used as bioactive agent carriers and methods of making thereof.
Many biologically active molecules such as anti-viral agents, anti-cancer agents, peptides/proteins and DNA, effective for a variety of therapeutic applications, have become commercially available through advances in recombinant DNA and other technologies. However, an ideal carrier for drugs and active agents is always needed to facilitate their solubility, delivery and effectiveness.
Cyclodextrins (CDs) are cyclic oligosaccharides, usually consisting of six to eight glucose units, which have a truncated cone shape with the wide open side being formed by secondary hydroxyl groups (2-OHs and 3-OHs) and the narrower side by primary hydroxyl groups (6-OHs). Cyclodextrins provide for unique micro-heterogenous environments since the exterior of the molecule is hydrophilic while the cavity is hydrophobic due to the relatively high electron density. The inclusion properties of cyclodextrins, namely, complex-formation between a guest molecule and a cyclodextrin molecule, have been extensively investigated. The complexes, which are formed in the solid state and in solution, consist of guest molecules which are held in the cavity of the host cyclodextrin and are stabilized by Van der Waals forces, and, to a lesser extent, by dipole-dipole interactions. Inclusion complexes in aqueous solutions are thought to be further stabilized by hydrophobic interactions, i.e., by the tendency of solvent water to push hydrophobic solutes of suitable size and shape into the essentially hydrophobic cavity, in order to attain the “most probable structure” of the solvent and obtain minimal energy in the overall system.
Practical use of natural cyclodextrins (α-, β-, and γ-CDs) as drug carriers is restricted by their low aqueous solubility. Safety is another major concern of cyclodextrins being used as drug carriers due to the toxicity of CD. Modification of the parent cyclodextrin to improve safety while maintaining the ability to form inclusion complexes with various substrates has been the goal of numerous research groups. Some groups have also focused on improving interaction between the pharmaceuticals and the cyclodextrins while others have attempted to prepare materials that can be chemically defined more precisely.
The two most promising cyclodextrin derivatives which are suitable for parenteral administration are hydoxylpropyl β-cyclodextrin (HPβCD or HPCD) and sulfobutylether-β-cyclodextrin (SBEβCD or SBE-CD). HPβCD has generally been found to be safe when administered parenterally in animals and humans [Pitha et al, J Pharm Sci, 84 (8), 927-32 (1995)]. Minor reversible histological changes have been observed in high dose animal studies (100-400 mg/kg) and more significant hematological changes were observed in these high dose studies suggesting red blood cell damage had occurred. No adverse effects were observed in human studies. SBEβCD has also been found to be safe when administered parenterally in mice [Rajewski et al, J Pharm Sci, 84 (8), 927-32 (1995)]. However, like most of the modified cyclodextrins, the binding constant between drugs and HPβCDs is usually less than those with the parent or unmodified cyclodextrin. Due to steric hindrance of the host molecule, the higher the degree of hydroxylpropyl substitution the poorer the drug binding.
Hydrophobic modifications of cyclodextrins have also been prepared in attempts to improve the formulations of some CD inclusionable drugs. It was found that partial methylation of the hydroxyl groups at the 2- and 6-position of β-cyclodextrin (DM-βCD or DMCD) generally leads to stronger drug binding due to increased hydrophobic interactions. Although the methylated cyclodextrins are highly water soluble, they also have greater toxicity. The toxicity of DMβCD was reduced significantly by modifying the free 3-hydroxyl groups with acetyl groups. This indicates that water-soluble cyclodextrin derivatives with superior bioadaptability and inclusion ability can be prepared by carefully selecting the substitution groups. Controlling the degree of substitution is also important in balancing water solubility and complexing capability. When the substitution groups are more hydrophobic than methyl groups, such as an ethyl group, an acetyl group, etc., the whole cyclodextrin derivative becomes practically water insoluble. These compounds have been shown to have potential application as sustained release carriers for water-soluble drugs. Among the alkylated cyclodextrins, heptakis(2,6-di-O-ethyl)-β-cyclodextrin and heptakis(2,3,6-tri-ethy)-β-cyclodextrin were the first slow-release carriers to be used in conjunction with water soluble diltiazem, isosorbide dinitrate, and the peptide buserelin acetate.
On the other hand, the peracylated cyclodextrins with medium alkyl chain lengths (C4-C5) are particularly useful as novel hydrophobic carriers due to their multifunctional and bioadaptable properties. They have broad applicability for various routes of administration: for example, the bioadhesive properties of heptakis(2,3,6-tri-O-butanoyl-β-cyclodextrin (C4) can be used in oral and transmucosal formulations, while the film-forming properties of heptakis (2,3,6-tri-O-valeryl)-β-cyclodextrin (C5) are useful in transdermal preparations. In oral applications, the release of molsidomine, a water-soluble and short-half life drug, was markedly retarded by complexation with peracylated-β-cyclodextrins in decreasing order of their solubility, particularly by those having carbon chains longer than the butylated derivatives. When the complexes were administered orally to beagle dogs, heptakis(2,3,6-tri-O-butanoyl)-β-cyclodextrin suppressed the peak plasma level of molsidomine and maintained a sufficient drug level for a long period, while use of other derivatives having shorter or longer chains than heptakis(2,3,6-tri-O-butanoyl)-β-cyclodextrin proved to be insufficient. This indicates that heptakis(2,3,6-tri-O-butanoyl)-β-cyclodextrin may be a useful carrier for orally administered water-soluble drugs, especially for drugs which are metabolized in the GI tract. The superior and sustained effect exhibited with the heptakis (2,3,6-tri-O-butanoyl)-β-cyclodextrin may be a result of both increased hydrophobicity and mucoadhesive properties. Because of its hydrophobicity, heptakis(2,3,6-tri-O-butanoyl)-β-cyclodextrin, as well as other hydrophobic cyclodextrin derivatives, can only be used in solid or oily formulations. On the other hand, like natural β-cyclodextrin, their membrane toxicity, which causes tissue irritation and hemolysis in a concentration-dependent manner is another limitation of their pharmaceutical application. For example, the concentration of DM-β-CD that induces 50% hemolysis of human erythrocytes is lower than that of so called bioadaptable CD derivatives such as 2-hydroxypropyl-β-CD, sulfobutyl ether of β-CD, and maltosyl-β-CD. The hemolytic activity of cyclodextrins is associated with the extraction of membrane components, mainly through inclusion action with cholesterol. However, this drawback can be overcome by further structural modification of alkylated CDs, for example, heptakis (2,6-di-O-methyl-3-O-acetyl)-β-CD (DMA-β-CD) was found to have much weaker hemolytic activity while keeping a similar inclusion ability to that of DM-β-CD [Hirayama et al, J Pharm Sci, 88 (10), 970-5 (1999)]. Since cyclodextrins are poorly adsorbed from the GI tract following oral administration, the oral administration of cyclodextrins raises minimal safety concerns that may result from the systemic absorption of the cyclodextrins themselves. However, cyclodextrins may cause secondary systemic effects through increased GI elimination of certain nutrients and bile acids. This effect is most notable for γ-cyclodextrin assisted fecal elimination of bile acids. The increased elimination, however, was only observed at very high oral doses of cyclodextrin (up to 20% of diet). The secondary effects of the increased bile acid elimination are increased conversion of serum cholesterol to the bile acids with subsequent lowering of plasma cholesterol levels.
For years, various kinds of cyclodextrins have been prepared to improve the physicochemical properties and inclusion capabilities of parent cyclodextrins, and some of the pharmaceutical products containing cyclodextrins have been approved. Because large amounts of cyclodextrins are necessary to alter the solubility properties of the drugs being carried, the toxicity of the cyclodextrin needs to be very low in order to safely delivery the necessary dose of a drug. Therefore either reducing the total dose or reducing the intrinsic toxicity of cyclodextrins can widen the pharmaceutical applications of cyclodextrins.
In view of the foregoing, it will be appreciated that providing improved cyclodextrin containing bioactive agent carriers and a method of using them would be a significant advancement in the art.